The use of antibodies to the CD20 antigen as diagnostic and/or therapeutic agents for diseases such as B-cell lymphoma has previously been reported. CD20 is a useful marker or target for B-cell lymphomas as this antigen is expressed at very high densities on the surface of malignant B-cells, i.e., B-cells wherein unabated proliferation can lead to B-cell lymphomas.
CD20 (also known as Bp35) is a B-lymphocyte-restricted differentiation antigen that is expressed during early pre-B-cell development and remains until plasma cell differentiation. It is believed by some that the CD20 molecule may regulate a step in the B-cell activation process which is required for cell cycle initiation and differentiation. Moreover, as noted, CD20 is usually expressed at very high levels on neoplastic (“tumor”) B-cells. The CD20 antigen is appealing for targeted therapy, because it does not shed, modulate, or internalize.
Previous reported therapies involving anti-CD20 antibodies have involved the administration of a therapeutic anti-CD20 antibody either alone or in conjunction with a second radiolabeled anti-CD20 antibody, or a chemotherapeutic agent. The Food and Drug Administration has approved the therapeutic use of one such anti-CD20 antibody, RITUXAN for use in relapsed and previously treated low-grade non-Hodgkin's lymphoma (NHL). However, while the use of RITUXAN has generally been reported as effective for treating B-cell lymphomas, the treated patients are often subject to disease relapse.
More recently, RITUXAN was tested for safety, tolerability and preliminary clinical efficacy for the treatment of 18 patients with Systemic Lupus Erythematosus (SLE) (which are non immunosuppressed patients). Part of the results of this study were presented in October of 2002 at the American College of Rheumatology (ACR) 66th Annual Scientific Meeting. Of the 18 patients treated, six patients received one infusion of RITUXAN at 100 mg/m2 (low dose), six patients received one infusion of RITUXAN at 375 mg/m2 (medium dose), and six patients received four weekly infusions of RITUXAN at 375 mg/m2 (high dose). Three of the 12 patients that received the low or medium dose (25%) developed elevated human anti-chimera (HACA) titers at two months, while the high dose patients are still being evaluated.
Accordingly, what is needed, are CD20 binding molecules that have a high binding affinity and low dissociation constant such that treated B-cell lymphoma patients do not relapse, and CD20 binding molecules that do not cause, or have a reduced potential to cause, a HACA reaction when administered to patients who are not immunosuppressed.